tbuckley/cabot-search huggingface dataset:
Paradoxical Association of Hyperglycemia and Surgical Complications Among Patients With and Without Diabetes
Authors: Judy Y. Chen, Hasan Nassereldine, Sara B. Cook, Lucas W. Thornblade, E. Patchen Dellinger, David R. Flum
Journal: JAMA Surgery (2022)

Surgical complications associated with perioperative hyperglycemia are conventionally associated with diabetes, but, paradoxically, prior cohort studies have found that patients without diabetes have greater risk of complications at similar levels of hyperglycemia compared with patients with diabetes.To describe the association between perioperative hyperglycemia and surgical complications in a population of surgical patients without diabetes receiving routine blood glucose testing and insulin administration and to evaluate the potential correlation of perioperative hyperglycemia.This retrospective cohort study of National Surgical Quality Improvement Program-defined complications after operation took place at a single academic medical center hospital from January 2013 to October 2016. Consecutive patients undergoing general, vascular, and gynecologic operations who were expected to have at least a 48-hour admission were included. Hyperglycemia was defined as blood glucose level of 140 mg/dL or higher within 24 hours after surgery. Multivariate regression was used to assess the association of hyperglycemia and complications, stratified by hyperglycemia severity and adjusted for diabetes status. Analysis began in February 2022.Routine blood glucose testing and insulin administration.The main outcomes are odds of experiencing perioperative hyperglycemia and postoperative complication, comparing patients with and without diabetes.A total of 7634 patients (mean [SD] age, 53.5 [15.1] years; 6664 patients without diabetes [83.3%] and 970 patients with diabetes [17.7%]) underwent general (6204 [81.3%]), vascular (208 [2.7%]), and gynecologic (1222 [16%]) operations. Of these, 5868 (77%) had blood glucose testing (4899 individuals without diabetes [73.5%] and 969 [99.9%] with diabetes). Hyperglycemia occurred in 882 patients with diabetes (91%) and 2484 patients without diabetes (50.7%). Of those with blood glucose level more than 180 mg/dL, 1388 (72.7%) received insulin (658 patients with diabetes who had hyperglycemia [91%] and 680 patients without diabetes who had hyperglycemia [61%]). Adjusted odds of experiencing a complication were 83% greater for patients without vs with diabetes at blood glucose level of 140 to 179 mg/dL (odds ratio, 1.83 [95% CI, 0.93-3.6]), 49% greater for blood glucose level of 180 to 249 mg/dL (odds ratio, 1.49 [95% CI, 1.06-2.11]), and 88% greater for blood glucose level more than 250 mg/dL (odds ratio, 1.88 [95% CI, 1.11-3.17]). A similar trend was observed for serious complications. Insulin may mitigate the association of hyperglycemia and complications in patients without diabetes.In this study, with near universal blood glucose testing and frequent insulin use, patients without diabetes paradoxically had worse outcomes than patients with diabetes at similar levels of hyperglycemia. Insulin may mitigate this effect and broader use may improve outcomes.
Abstract 2358: Impact pathway analysis of FOXC2-correlated genes in melanoma: A meta-analysis approach to understand the tumor-promoting functions of the FOXC2 transcription factor
Authors: James B. Wall, Kristian M. Hargadon
Journal: Cancer Research (2022)

Abstract Melanoma is a cancer that arises from pigment-producing melanocytes in the skin. Because of the increasing incidence of melanoma and its resistance to many therapies, insights into melanoma progression are needed. FOXC2, a member of the forkhead box family of transcription factors, has been shown to have oncogenic activity in many epithelial cancer types, and we have recently reported a role for FOXC2 in melanoma progression as well. To gain insight into the role of FOXC2 in melanoma progression, we analyzed publicly available RNA-sequencing data from tumor biopsies of melanoma patients, including a cohort of 479 patients catalogued in The Cancer Genome Atlas as well as additional cohorts from other independent studies. We performed Spearman correlation analyses to identify genes positively and negatively co-expressed with FOXC2, and we performed Impact Pathway Analysis and Gene Ontology Analysis to determine which biological pathways and processes are most impacted by FOXC2-associated genes in melanoma. Our data highlight critical pathways impacted by the expression of FOXC2, and they identify specific genes influenced by this transcription factor that provide mechanistic insight into the oncogenic activity of FOXC2 in melanoma and potentially other cancers. Citation Format: James B. Wall, Kristian M. Hargadon. Impact pathway analysis of FOXC2-correlated genes in melanoma: A meta-analysis approach to understand the tumor-promoting functions of the FOXC2 transcription factor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2358.
Abstract 1417: A non-systemic phosphodiesterase-5 inhibitor for colon cancer prevention
Authors: Bianca N. Islam, Avelina Lee, Iryna Lebedyeva, Darren D. Browning
Journal: Cancer Research (2022)

Abstract Phosphodiesterase 5 inhibitors (PDE5i) are under investigation for potential repurposing as an intervention for colon cancer prevention. A drawback to conventional drugs in this class are drug-drug interactions and side-effects and that would be poorly tolerated when taken on a chronic basis for prevention. To address this issue we designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity. This modification did not affect pharmacology as malonyl-sildenafil had an IC50 of 1.8 nM, but exhibited almost 100-fold reduced cell entry compared to sildenafil. Using an LC-MS/MS approach, malonyl-sildenafil was undetectable in mouse plasma 1 hour after gavage, even at a dose up to 36 mg/kg, but was readily detected in the feces collected 2-4 hours after administration. This contrasted with sildenafil that was detected in the plasma, but not in the feces. While sildenafil exhibited the established Cmax at 1-2 hr, malonyl sildenafil was not detected in the plasma up to 24 hr after an oral dose of 9 mg/kg, but continued to be shed at high levels in the feces for up to 8 hrs. Treatment of mice with malonyl-sildenafil in the drinking water for 8 days was well-tolerated, and resulted in a suppression of proliferation in the colon epithelium that is consistent with results published previously for mice treated with PDE5i. Taken together, the results demonstrate that a carboxylic acid-containing analog of sildenafil prohibits systemic delivery but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generate a first in class drug for colon cancer chemoprevention. Citation Format: Bianca N. Islam, Avelina Lee, Iryna Lebedyeva, Darren D. Browning. A non-systemic phosphodiesterase-5 inhibitor for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1417.
Abstract 2386: Investigating cyclopamine tartrate as a potential suppressor of lung adenocarcinoma and squamous cell carcinoma
Authors: Eranda Berisha, Adnin Ashrafi, Maria Del Carmen Chacon Castro, Li Zhang
Journal: Cancer Research (2022)

Abstract Lung cancer is the leading cause of death by cancer, and non-small cell lung cancer comprises of 85-90% of lung cancer cases. Previous studies have demonstrated the importance of heme in mitochondrial metabolism and OXPHOS. Heme is an essential molecule in the oxidative phosphorylation pathway especially since Complex II-IV all contain heme. During lung tumorigenesis there is a marked increase in heme synthesis and uptake; other protein and enzymes relating to heme were also upregulated. Heme-sequestration proteins (HeSPs) have shown high effectiveness in suppressing the development and progression of lung adenocarcinoma and squamous cell carcinoma, therefore targeting heme using CycT should yield similar results. Previous studies have indicated that cyclopamine tartrate (CycT) can effectively arrest lung tumor growth and progression. CycT does this by inhibiting the levels of proteins and enzymes involved in heme uptake, synthesis, as well as reducing heme synthesis and degradation in adenocarcinoma. We therefore aim to examine the effectiveness of CycT in both, adenocarcinoma and squamous cell carcinoma.In vitro experiments using NSCLC adenocarcinoma cell line A549 and squamous cell carcinoma HCC15 are in progression with initial results supporting the hypothesis. Cell proliferation assays have shown a marked decrease in CycT-treated groups in both cell lines. Based on colony formation assays, results indicate that CycT inhibits colony formation. Heme synthesis and degradation have also shown the effectiveness of CycT in suppressing tumorigenesis in both cell types. Oxygen consumption rates of both cell types were examined with CycT inhibiting oxygen consumption. Overall, in vitro experiments support the idea that CycT can suppress or arrest lung adenocarcinoma and squamous cell carcinoma. Citation Format: Eranda Berisha, Adnin Ashrafi, Maria Del Carmen Chacon Castro, Li Zhang. Investigating cyclopamine tartrate as a potential suppressor of lung adenocarcinoma and squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2386.
Abstract 3995: Identification of perp as a tumor promoter in pancreatic cancer via the utilization of an aged model of cancer cachexia
Authors: Aneesha Dasgupta, Paige C. Arneson-Wissink, Rebecca E. Schmitt, Dong Seong Cho, Alexandra M. Ducharme, Tara L. Hogenson, Eugene W. Krueger, William R. Bamlet, Lizhi Zhang, Gina Razidlo, Martin E. Fernandez-Zapico, Jason D. Doles
Journal: Cancer Research (2022)

Abstract Cachexia is a multifactorial syndrome characterized by extensive body weight, lean muscle and fat mass loss. Cachexia worsens cancer patient prognoses and contributes to poor chemotherapy tolerance and response rates. About 80% of pancreatic cancer patients suffer from cachexia and one-third die due to cachexia-related complications such as respiratory failure and cardiac arrest. Although there has been considerable research into cachexia mechanisms and interventions, there are, to date, no FDA-approved cachexia therapies. A major contributing factor could be the failure of animal models to accurately recapitulate the human condition. In this study, we generated an aged murine model of pancreatic cancer cachexia to compare cachexia progression in young versus aged tumor-bearing mice. Comparative transcriptomic analyses of the muscles identified 3-methyladenine (3-MA), a known autophagy inhibitor, as a candidate anti-wasting compound. In vitro analyses confirmed anti-wasting effects while in vivo analysis demonstrated that 3-MA could rescue muscle wasting and suppress tumor growth. Surprisingly, transcriptome analyses of 3MA-treated tumor cells did not reveal autophagy-related signatures but instead implicated Perp as a novel 3-MA target. Probing further, we 1) observed significantly higher expression of Perp in pancreatic cancer cell lines compared to control cells, 2) noted a survival disadvantage associated with elevated PERP in the TCGA database, 3) found that PERP knockdown in cancer cells led to reduced tumor proliferation, and 4) confirmed that 3-MA-associated Perp reduction inhibited tumor growth. Moreover, we also demonstrate that survival benefits associated with 3MA is independent of tumor progression. Finally, we queried Perp expression in human tumor samples and observed increased Perp expression in adenocarcinoma regions compared to tumor adjacent tissue. Taken together, we report a novel mechanism linking 3-MA to Perp inhibition, and further implicate Perp as a novel tumor promoting factor in pancreatic cancer. Citation Format: Aneesha Dasgupta, Paige C. Arneson-Wissink, Rebecca E. Schmitt, Dong Seong Cho, Alexandra M. Ducharme, Tara L. Hogenson, Eugene W. Krueger, William R. Bamlet, Lizhi Zhang, Gina Razidlo, Martin E. Fernandez-Zapico, Jason D. Doles. Identification of perp as a tumor promoter in pancreatic cancer via the utilization of an aged model of cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3995.
Abstract LB162: Human herpesvirus 8 infection is associated with prostate cancer among <i>IFNL4-ΔG</i> carriers
Authors: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs
Journal: Cancer Research (2022)

Abstract Background: Chronic inflammation as seen with chronic infections, has been proposed as a risk factor for prostate cancer. Numerous studies failed to identify a specific microbial agent associated with prostate cancer risk. We have previously reported that human herpesvirus 8 (HHV-8) is associated with increased prostate cancer risk in Tobago; a population that is 97% of African ancestry. This association was not found in several studies of US men, who were predominately of European American ancestry. It is unclear if the discrepancies between US and Tobago men are due to differences in HHV-8 seroprevalence rates or ancestry-related genetics. Previous studies have reported that the dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene encoding interferon λ4 is more prevalent among individuals of African ancestry and impairs viral clearance. In this study, we investigated whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent. Methods: We investigated the association of HHV-8 seropositivity with prostate cancer in 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based control men from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT). Results: HHV-8 seropositivity was higher in cases than controls (OR 1.76; 95%CI: 1.20 - 2.59). The association of HHV-8 seropositivity with prostate cancer was restricted to carriers of the ΔG allele (OR 2.19: 95%CI: 1.38 - 3.48). HHV-8 seropositivity did not associate with prostate cancer among TT/TT genotype carriers (OR 1.03: 95%CI: 0.51 - 2.11). Further stratification by race/ethnicity showed that HHV-8 is associated with prostate cancer exclusively among carriers of the ΔG allele in both European American (OR 2.59; 95%CI: 1.20 - 5.56) and African American men (OR 1.96; 95%CI: 1.08 - 3.56). Conclusions: HHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant. Impact: The study establishes IFNL4-ΔG as a candidate prostate cancer risk factor in men with an HHV-8 infection. This gene-environment association of IFNL4-ΔG with prostate cancer should be further evaluated using prospective study designs. Citation Format: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB162.
Abstract 111: Head and neck cancer cells can differentiate and resemble their tissue of origin
Authors: Felix Oppel, Senyao Shao, Sarah Gendreizig, Philipp Kühnel, Vivien Przybycin, Carsten Hain, Pascal Schmidt, Matthias Schürmann, Peter Goon, Karsten Niehaus, Jörn Kalinowski, Holger Sudhoff
Journal: Cancer Research (2022)

Abstract Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease with a mortality rate of about 50%. It represents the sixth most common type of malignant tumor in the world. Risk factors include tobacco and alcohol usage and infection with the human papilloma virus (HPV). HPV-negative HNSCCs frequently display areas of cornification evident by keratin pearls in the tumor tissue. Cornification represents a natural differentiation path of keratinocytes in the normal epidermis and oral mucosa. To investigate the mechanisms of HNSCC cell differentiation we have established spheroid cell cultures from patient-derived HNSCC and parotid gland adenoid cystic carcinoma (ACC) tissue that grow in suspension under serum-free conditions. The use of a specific differentiation medium induced striking adhesion, loss of proliferation, and differentiation in tumor cells. Spheroid cells grew as single cell clones under serum-free conditions with a cloning efficiency of 40-60%, which was fully diminished under differentiating conditions. HNSCC cells cornified as indicated by the formation of lamellar bodies in the cytoplasm of adherent cells and an upregulation of cornification markers SPRR3 and involucrin. ACC cells upregulated parotid gland differentiation markers including α-amylase. RNA-seq analysis in HNSCC cells confirmed an upregulation of signaling pathways associated with cornification and epithelial cell differentiation. Conversely, pathways regulating the three-dimensional organization of the genome were downregulated upon differentiation. This was accompanied by the formation of ATRX-positive heterochromatin foci in the nucleus of differentiated ACC and HNSCC cells resembling those previously described to arise during therapy-induced senescence. Moreover, gas chromatography mass spectrometry analysis revealed a lack of essential amino acids including leucine to be implicated in the differentiation process. Altogether, our spheroid model of HNSCC and ACC cells is suitable to analyze the mechanisms underlying tumor cell differentiation and might lead to new therapeutic approaches that can drive long-term repopulating HNSCC and ACC cells into differentiation. Citation Format: Felix Oppel, Senyao Shao, Sarah Gendreizig, Philipp Kühnel, Vivien Przybycin, Carsten Hain, Pascal Schmidt, Matthias Schürmann, Peter Goon, Karsten Niehaus, Jörn Kalinowski, Holger Sudhoff. Head and neck cancer cells can differentiate and resemble their tissue of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 111.
Abstract 1580: Cancer cells promote phenotypic alterations in adjacent hepatocytes to facilitate vessel co-option in colorectal cancer liver metastasis
Authors: Miran Rada, Anthoula Lazaris, Peter Metrakos
Journal: Cancer Research (2022)

Abstract Vessel co-option is associated with resistance against anti-angiogenic therapy in colorectal cancer liver metastases (CRCLM). Vessel co-opted lesions are characterized by highly motile cancer cells that move toward and along the pre-existing vessels in the surrounding non-malignant tissue and hijack them to gain access to nutrient. In order to access the sinusoidal vessels, the cancer cells must displace the hepatocytes and occupy their space. However, the mechanisms underlying this displacement are unknown. Herein, we examined the involvement of apoptosis, motility, epithelial-mesenchymal transition (EMT) and autophagy pathways in hepatocyte’s displacement by cancer cells. We demonstrated that cancer cells induce the expression of the proteins that associated with upregulation of apoptosis, motility and EMT in adjacent hepatocytes in vitro and in vivo. Accordingly, we observed upregulation of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and Actin Related Protein 2/3 (ARP2/3) in adjacent hepatocytes to cancer cells, while we noticed lower expression levels of E-cadherin. Importantly, Runt-related transcription factor 1 (RUNX1) knockdown in the cancer cells has impaired their function towards adjacent hepatocytes in vitro and in vivo. Altogether, our data indicating that cancer cells may exploit various mechanisms to displace the hepatocytes and access to the sinusoidal vessels to establish vessel co-option. Citation Format: Miran Rada, Anthoula Lazaris, Peter Metrakos. Cancer cells promote phenotypic alterations in adjacent hepatocytes to facilitate vessel co-option in colorectal cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1580.
Abstract 2414: Retinoic acid induced 14 drives pancreatic cancer progression and metastasis
Authors: Farhana Runa, Luke Tomaneng, Yvess Adamian, Nathan Cox, Albert-Fred Aquino, Matthew Wallace, Carolina Gonzalez, Kishan Bhakta, Malachia Hoover, Laurelin Wolfenden, Jonathan D. Humphries, Martin J. Humphries, Michael Boyce, Jonathan A. Kelber
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with very poor outcomes - fewer than 10 percent of patients survive beyond five years after diagnosis. The primary hurdles facing PDAC patients and clinicians are early dissemination, a lack of therapeutic targets and desmoplasia that renders the primary tumor refractory to chemotherapy. In this regard, we have previously reported that pseudopodium-enriched atypical kinase 1 (PEAK1) and integrin α1 (ITGA1) mediate gemcitabine resistance and metastasis in PDAC. To identify new mechanisms of PDAC progression, we mined the Cancer BioPortal and Human Cell Map BioID databases for additional pseudopodium-enriched (PDE) proteins that predict poor patient outcomes, correlate with PEAK1 and ITGA1 expression in PDAC, and interact with PEAK1 and ITGA1. Here, we identify Retinoic Acid Induced 14 (RAI14, Ankycorbin or NORPEG) as a new candidate driver of PDAC that is a constituent of the KRasG12D PDAC cell autonomous phosphoproteome, localizes to cytoskeleton/adhesion domains in PDAC cells and correlates in expression with ITGA1-binding collagens in PDAC. Knockdown or knockout of RAI14 in KRas mutant PDAC cells impaired adhesion-dependent proliferation/survival in vitro and tumor growth and metastasis in vivo. Single cell cyclic immunofluorescence (CycIF) further revealed that RAI14 supports a subpopulation of PDAC cells positive for proliferation, epithelial to mesenchymal transition (EMT) and antiapoptotic programs. By using a RAI14-focused bioinformatics pipeline in combination with proteomic and immunofluorescence data on the composition of ITGA1-dependent adhesion complexes in PDAC cells, we identified Polo-Like Kinase 1 (PLK1) as a candidate that may control RAI14 function and adhesion-regulated mitosis during PDAC progression. Notably, the potency of volasertib, a PLK1-specific inhibitor, was reduced in RAI14 knockout cells, supporting a model in which RAI14 mediates adhesion-dependent PLK1 functions in PDAC. Taken together, these studies uncover a mechanism for RAI14-driven PDAC progression and the development of strategies to increase chemotherapy sensitivity, reduce primary/metastatic tumor burden and improve patient outcomes. Citation Format: Farhana Runa, Luke Tomaneng, Yvess Adamian, Nathan Cox, Albert-Fred Aquino, Matthew Wallace, Carolina Gonzalez, Kishan Bhakta, Malachia Hoover, Laurelin Wolfenden, Jonathan D. Humphries, Martin J. Humphries, Michael Boyce, Jonathan A. Kelber. Retinoic acid induced 14 drives pancreatic cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2414.